Progressive cognitive impairment can occur in up to 50% of primary and metastatic brain tumor patients surviving e6 months after treatment with fractionated partial or whole-brain irradiation (fWBI);~200,000 patients/year receive brain irradiation. Although short-term clinical interventions can modulate cognitive impairment, there are no proven long-term treatments or preventive strategies for this radiation-induced morbidity. Rodent models have provided, i] important insights into the pathogenesis of radiation-induced brain injury, and ii] the rationale for anti-inflammatory-based therapeutic approaches, including blockade of the renin- angiotensin system. However, translation of these results to the clinic is limited by concerns about their applicability to humans. Rodents have a brain structure and organization that is very different from humans, and they do not have the higher-order executive functions most often diminished in patients after brain irradiation. Nonhuman primates (NHP) are much less likely to display these limitations when used for preclinical investigations. Indeed, we have developed a NHP model in which fWBI of adult male rhesus monkeys leads to, i] progressive decline in higher-order executive functions, ii] decreased glucose uptake measured by FDG-PET in brain areas involved in task performance prior to fWBI, iii] increased glucose uptake in brain areas previously not involved in the task prior to fWBI, and iv] histopathological and MRI changes that parallel those seen in the irradiated human brain. Thus, we hypothesize that the longitudinal cognitive, intervention, and mechanistic data obtained with this novel NHP model of radiation-induced higher order cognitive impairment will translate faster and more reliably to the clinic than similar rodent data. To test this hypothesis, we propose the following Specific Aims using our NHP model. We will, 1] identify imaging biomarkers and potential mechanisms for the onset and progression of radiation-induced cognitive impairment using FDG-PET and MRI techniques, 2] determine if administration of the angiotensin type 1 receptor antagonist (AT1RA), olmesartan, prior to, during, and for 6 months after fWBI can permanently prevent or ameliorate radiation-induced cognitive impairment and modulate the brain injury assessed by noninvasive imaging techniques during the first year postirradiation, and 3] determine if a 6 month administration of the AT1RA, olmesartan, starting at a postirradiation time when higher-order cognitive function is impaired, can prevent or ameliorate additional radiation-induced cognitive impairment and modulate the brain injury assessed by noninvasive imaging techniques over, i] 6 months of treatment, and ii] an additional 6 months after stopping treatment. Successful completion of these aims should provide new information about the onset and progression of radiation-induced cognitive impairment, and enable us to translate these findings faster and more reliably into clinical trials designed to enhance the long-term survival and QOL of cancer patients receiving fWBI.

Public Health Relevance

Approximately 100,000 cancer patients per year survive long enough after fractionated partial or whole-brain irradiation (fWBI) to develop radiation-induced cognitive impairment;no proven long-term treatments or preventive strategies are currently available. Using our nonhuman primate model, we will determine if blockade of the renin-angiotensin system can protect against or mitigate radiation-induced higher-order cognitive impairment. The results should allow us to translate these findings faster and more reliably into clinical trials designed to enhance the long-term survival and quality of life of cancer patients receiving fWBI.